The FDA has granted approval to treosulfan (Grafapex), in combination with fludarabine, as a preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHSCT) for adult and pediatric patients aged 1 year and older with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). This decision marks a significant advancement in conditioning options prior to stem cell transplantation for these patient populations.
The approval is primarily based on the results of the phase 3 MC-FludT.14/L Trial II (NCT00822393), a randomized, active-controlled study comparing treosulfan plus fludarabine to busulfan plus fludarabine. The trial enrolled 570 patients with AML or MDS who were considered at increased risk for standard myeloablative conditioning. Eligible patients included adults aged 18 to 70 years with AML or MDS, a Karnofsky performance status ≥ 60%, and age ≥ 50 years or a hematopoietic cell transplantation comorbidity index score > 2.
The study's primary efficacy outcome was overall survival (OS). Results indicated that patients in the treosulfan arm experienced a statistically significant improvement in OS compared to those in the busulfan arm (HR, 0.67; 95% CI, 0.51-0.90). Subgroup analyses also demonstrated a favorable trend towards improved OS in patients with AML (HR, 0.73; 95% CI, 0.51-1.06) and MDS (HR, 0.64; 95% CI, 0.40-1.02).
Key Trial Findings
In the treosulfan cohort, the 2-year event-free survival (EFS) rate was 64.0% (95% CI, 56.0-70.9) compared to 50.4% (95% CI, 42.8-57.5) in the busulfan cohort (HR, 0.65; 95% CI, 0.47-0.90; P < 0.0001 for non-inferiority and P = 0.0051 for superiority). The median follow-up was 15.4 months for patients treated with treosulfan and 17.4 months for patients treated with busulfan.
Notably, patients who received treosulfan also had lower rates of transplantation-related mortality (12.1% vs 28.2%, P=0.020) and non-relapse mortality (11.4% vs 22.6%, P=0.053) compared with patients who received busulfan. The 2-year relapse rates were similar between the two groups (24.6% vs 23.3%, respectively, P=0.50).
Safety Profile
The most common adverse events (occurring in ≥ 20% of patients) in the treosulfan arm were musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting. Selected grade 3 or 4 non-hematologic laboratory abnormalities were increased gamma-glutamyl transferase, bilirubin, alanine aminotransferase, aspartate aminotransferase, and creatinine.
Clinical Perspective
"This FDA approval provides a useful option for adult and pediatric patients, with the potential to enhance overall survival while minimizing side effects," said Filippo Milano, MD, PhD, of the Fred Hutch Cancer Center in Seattle. He added that this regimen could significantly improve outcomes for patients undergoing allo-HSCT for AML and MDS.
The recommended dose of treosulfan is 10 g/m2 daily on days -4, -3, and -2 combined with fludarabine 30 mg/m2 daily on days -6, -5, -4, -3, and -2, followed by alloHSCT infusion on day 0.
